title: Maternal protein restriction elevates cholesterol in adult rat offspring due to repressive changes in histone modifications at the cholesterol 7alpha-hydroxylase promoter.
abstract: Adverse events in utero, such as intrauterine growth restriction (IUGR), can permanently alter epigenetic mechanisms leading to the metabolic syndrome, which encompasses a variety of symptoms including augmented cholesterol. The major site for cholesterol homeostasis occurs via the actions of hepatic cholesterol 7α-hydroxylase (Cyp7a1), which catabolizes cholesterol to bile acids. To determine whether posttranslational histone modifications influence the long-term expression of Cyp7a1 in IUGR, we used a protein restriction model in rats. This diet during pregnancy and lactation led to IUGR offspring with decreased liver to body weight ratios, followed by increased circulating and hepatic cholesterol levels in both sexes at d 21 and exclusively in the male offspring at d 130. The augmented cholesterol was associated with decreases in the expression of Cyp7a1. Chromatin immunoprecipitation revealed that this was concomitant with diminished acetylation and enhanced methylation of histone H3 lysine 9 [K9,14], markers of chromatin silencing, surrounding the promoter region of Cyp7a1. These epigenetic modifications originate in part due to dietary-induced decreases in fetal hepatic Jmjd2a expression, a histone H3 [K9] demethylase. Collectively, these findings suggest that the augmented cholesterol observed in low-protein diet-derived offspring is due to permanent repressive posttranslational histone modifications at the promoter of Cyp7a1. Moreover, this is the first study to demonstrate that maternal undernutrition leads to long-term cholesterol dysregulation in the offspring via epigenetic mechanisms.
authors.affiliation: The Department of Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada, N6A 5C1.
authors.forename: Gurjeev
authors.initials: G
authors.lastname: Sohi
authors.forename: Kelly
authors.initials: K
authors.lastname: Marchand
authors.forename: Andrew
authors.initials: A
authors.lastname: Revesz
authors.forename: Edith
authors.initials: E
authors.lastname: Arany
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Hardy
mesh_terms: D000107:Acetylation; D000818:Animals; D001835:Body Weight / Q000235:genetics; D002784:Cholesterol / Q000097:blood*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics*; D018753:Diet, Protein-Restricted; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D007774:Lactation; D008099:Liver / Q000254:growth & development / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena / Q000235:genetics*; D008745:Methylation; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D002784:Cholesterol; D056484:Jumonji Domain-Containing Histone Demethylases; D002790:Cholesterol 7-alpha-Hydroxylase; D012319:RNA Polymerase II